Although converging evidence from different levels of analyses supports the conception of fear and anxiety as distinct phenomena, little is known about the distinguishing features of these two aversive states. Both fear and anxiety are responses to threat. However, while fear is a phasic response to a clearly identifiable and imminent threat, anxiety is a sustained aversive state of apprehensive anticipation of future potential threats. Our working hypothesis is that fear and anxiety can be modeled by cued fear and contextual fear, respectively. The distinction between cued fear and contextual anxiety was first made in fear conditioning studies in animals. Cued fear is elicited by an explicit stimulus (e.g., a light) that predicts an imminent noxious stimulus (e.g., a shock). Contextual fear is caused by the experimental context (i.e., the cage, the experimental room) where an aversive experiment took place. Given the potential relevance of contextual fear for our understanding of anxiety disorders and the paucity of human research in this area, we are pursuing several areas of investigations focusing on contextual fear. First, our approach always begins with the development of experimental models, which are strongly influence by clinical data and theories. In order to develop meaningful procedures we have embarked on projects that use computer-generated virtual reality to investigate Pavlovian fear conditioning. Keys advantages of virtual reality include the possibility to study conditioning to spatial environment (context conditioning) and behavioral avoidance, a hallmark of anxiety disorders. Second, we examine factors that are involved in the modulation of contextual fear and how experimental contexts influence fear responses to discrete cues using renewal designs. We have reported in several studies that predictability mitigates contextual fear. Contextual fear is increased by unpredictability as long as the aversive event is sufficiently unpleasant. We are currently following-up on these findings in three areas. One investigates brain mechanisms mediating cued fear to signaled shocks and contextual anxiety to unpredictable shock in fMRI and PET studies. Results indicate distinct neural system involved in phasic cued fear and sustained anxiety to unpredictable shocks. Studies of cued and context conditioning in virtual reality environments confirm the preclinical data. They show that the hippocampus is involved in context conditioning. A second set of investigations is aimed at validating clinically and psychopharmacology our experimental models of anxiety. Evidence now show that patients with panic disorder exhibit enhanced contextual anxiety but not phasic cued fear. Similarly, sustained anxiety to contextual threat, but not fear to a discrete cue, is reduced by treatment with established anxiolytics, such as the benzodiazepine alprazolam. SSRI are the treatment of choices for certain anxiety disorders but their efficacy develops only after chronic treatment. In fact, SSRI can be anxiogenic in some patients initially. Our experimental model can detect these opposite effects after acute and chronic treatment. The main new area of investigations includes mechanisms that promote contextual fear such as stimulus generalization and stress. We have developed a procedure to test the generalization of fear across stimuli that share similar physical characteristics and are currently testing patients with PTSD and panic disorder.